title: Activated protein C inhibits proliferation and tumor necrosis factor α-stimulated activation of p38, c-Jun NH2-terminal kinase (JNK) and Akt in rheumatoid synovial fibroblasts.
abstract: Synovial fibroblast proliferation is a hallmark of the invasive pannus in the rheumatoid joint. Activated protein C (APC) is a natural anticoagulant that exerts antiinflammatory and cyto-protective effects in various diseases via endothelial protein C receptor (EPCR) and proteinase-activated receptor (PAR)-mediated pathways. In this study, we investigated the effect and the underlying cellular signaling mechanisms of APC on proliferation of human rheumatoid synovial fibroblasts (RSFs). We found that APC stimulated proliferation of mouse dermal fibroblasts (MDFs) and normal human dermal fibroblasts (HDFs) by up to 60%, but robustly downregulated proliferation of RSFs. APC induced the phosphorylation of extracellular signal-regulated protein kinase (ERK) and enhanced expression of p21 and p27 in a dose-dependent manner in RSFs. The latter effect was inhibited by pre-treatment with the ERK inhibitors PD98059 and U0126 but not by p38 inhibitor SB203580. In addition, APC significantly downregulated tumor necrosis factor (TNF)α-stimulated cell proliferation and activation of p38, c-Jun NH2-terminal kinase (JNK) and Akt in RSFs. These results provide the first evidence that APC selectively inhibits proliferation and the inflammatory signaling pathways of RSFs. Thus, APC may reduce synovial hyperplasia and pannus invasion in rheumatoid arthritis.
authors.affiliation: Sutton Arthritis Research Laboratories, Sydney Medical School, The University of Sydney at Royal North Shore Hospital, St Leonards, Australia.|Department of Surgery, Kolling Institute of Medical Research, Sydney Medical School, The University of Sydney at Royal North Shore Hospital, St Leonards, Australia.
authors.forename: Sohel M
authors.initials: SM
authors.lastname: Julovi
authors.affiliation: Sutton Arthritis Research Laboratories, Sydney Medical School, The University of Sydney at Royal North Shore Hospital, St Leonards, Australia.
authors.forename: Kaitlin
authors.initials: K
authors.lastname: Shen
authors.affiliation: Sutton Arthritis Research Laboratories, Sydney Medical School, The University of Sydney at Royal North Shore Hospital, St Leonards, Australia.
authors.forename: Kelly
authors.initials: K
authors.lastname: Mckelvey
authors.affiliation: Sutton Arthritis Research Laboratories, Sydney Medical School, The University of Sydney at Royal North Shore Hospital, St Leonards, Australia.
authors.forename: Nikita
authors.initials: N
authors.lastname: Minhas
authors.affiliation: Sutton Arthritis Research Laboratories, Sydney Medical School, The University of Sydney at Royal North Shore Hospital, St Leonards, Australia.
authors.forename: Lyn
authors.initials: L
authors.lastname: March
authors.affiliation: Sutton Arthritis Research Laboratories, Sydney Medical School, The University of Sydney at Royal North Shore Hospital, St Leonards, Australia.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Jackson
mesh_terms: D000368:Aged; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000473:pathology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D020405:Dermis / Q000166:cytology*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D011486:Protein C / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D011486:Protein C; D014409:Tumor Necrosis Factor-alpha